The search for odorant receptors

  • Buck L
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The Question The first time I thought about olfaction was when I read a 1985 paper from Sol Snyder's group that discussed the unsolved question of how odors are detected in the nose (Pevsner et al., 1985). This paper opened up a fascinating new world for me. It was estimated that hu-mans could perceive 10,000 or more chemicals as hav-ing distinct odors. Even more remarkably, subtle changes in an odorous chemical could dramatically change its perceived odor. How could the olfactory sys-tem detect such an enormous diversity of chemicals? And how could the nervous system translate this com-plexity of chemical structures into a multitude of differ-ent odor perceptions? To me, this was a monumental problem and a wonderful puzzle. I was hooked. As a molecular biologist, the logical first question to ask was how the recognition of diverse chemical struc-tures is accomplished in the nose. With this knowledge in hand, one might then be able to explore how sensory information is organized in the nose and the brain to ultimately yield odor perceptions. It seemed obvious from a molecular standpoint that there must be a family of odorant receptors that varied in ligand specificity. It also seemed that olfactory sensory neurons in the nose that detect odorants must express different receptors in order for odorants to elicit different signals in the brain and thereby generate distinct odor perceptions. The Search In March 1988, I embarked on a search for odorant receptors; this search would prove arduous, but im-mensely rewarding. At the time, I had already completed a postdoctoral project in Richard Axel's lab on Aplysia neurons. My background was in immunology and I had also been trying to develop a method to identify re-arranged genes in the mammalian nervous system, the idea being that such genes might provide insight into its cellular and connectional diversity. I was intrigued by the possibility that gene rearrangement or gene con-version might be involved in the generation of a varied set of odorant receptors or regulate their expression, as with antigen receptors in the immune system. I became obsessed with finding the odorant receptors and stayed on in Richard Axel's lab to look for them. I first looked for clues as to the molecular nature of the receptors. Odorants were reported to induce GTP-dependent increases in adenylyl cyclase activity in the cilia of olfactory sensory neurons (the apparent site of odorant recognition), suggesting a role for G proteins and cAMP in olfactory transduction (Pace et al., 1985; Sklar et al., 1986). Moreover, the cilia had cyclic nucleo-*Correspondence:




Buck, L. B. (2004). The search for odorant receptors. Cell, 116, S117–S120.

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